2-phosphono-3-amino acrylic acid esters

ABSTRACT

Reagents for aldehyde synthesis, particularly for formylolefination, of the general formula:   WHEREIN R1 represents a lower alkyl group, R2 represents R1O or an alkyl, aralkyl or aryl group, R3 represents an acyclic or cyclic alkyl or aryl group, and R4 represents a hydrogen atom, an alkyl, aralkyl or alkoxycarbonyl group or a halogen atom, which react with carbonyl compounds   TO YIELD Alpha , Beta -UNSATURATED ALDEHYDES OF THE GENERAL FORMULA:   WHEREIN R4 has the same meaning as described above.

United States Patent [191 Nagata et a1.

[ 2-PHOSPHONO-3-AMINO ACRYLIC ACID ESTERS [75] Inventors: Wataru Nagata, Nishinomiya;

Yoshio Hayase, Sakai, both of Japan [73] Assignee: Shionogi & Co., Ltd., Higashi-ku,

Osaka, Japan [22] Filed: Apr. 7, 1972 [21] Appl. No.: 242,206

Related US. Application Data [62] Division of Ser. No. 803,106, Feb. 27, 1969, Pat. No.

[30] Foreign Application Priority Data Mar. 7, 1968 Japan 43-14901 Mar. 19, 1968 Japan 43-18134 Mar. 19, 1968 Japan 43-18135 Mar. 30, 1968 Japan 43-20805 [52] US. Cl .1 260/941, 260/239.55 C, 260/397.3,

Primary ExaminerAnton H. Sutto Attorney, Agent, or Firm-Wenderoth, Lind & Ponack Mar. 26, 1974 5 7] ABSTRACT Reagents for aldehyde synthesis, particularly for formyl-olefination, of the general formula:

wherein R represents a lower alkyl group, R represents RO or an alkyl, aralkyl or aryl group, R represents an acyclic or cyclic alkyl or aryl group, and R represents a hydrogen atom, an alkyl, aralkyl or alkoxycarbonyl group or a halogen atom, which react with carbonyl compounds to yield a,B-unsaturated aldehydes of the general formula:

wherein R has the same meaning as described above.

2 Claims, No Drawings zPHosPHoNoe-AMrNoACRYLIC ACID ESTERS This is a division of application Serial No. 803,106 filed February 27, 1969, now US. Patent No. 3,673,284.

The present invention relates to novel reagents for aldehyde synthesis, to processes for the preparation thereof and to uses thereof.

More particularly, the present invention relates to novel reagents for formyl-olefination represented by the general formula:

wherein R is a lower alkyl group, R is a member se lected from the group consisting of R 0, a lower alkyl group, an aralkyl group of seven to eight carbon atoms and an aryl group of six to seven carbon atoms, R is a member selected from the group consisting of an acyclic or cyclic alkyl group of one to six carbon atoms and an aryl group of six to seven carbon atoms, and R is a member selected from the group consisting of a hydrogen atom, a lower alkyl group, an aralkyl group of seven to eight carbon atoms, a lower alkoxycarbonyl group, and a halogen atom.

The methods for preparing a,B-unsaturated aldehydes, so-called formyl-olefination, consisting of adding two carbon atoms to carbonyl functions as illustrated by the accompanying equation, have widely been utilized as useful synthetic method in chemical or pharmaceutical industries, particularly in preparations of pharmaceutically useful compounds such as various steroids, vitamin A, vitamin D, carotenoids and other natural products or medicaments or intermediates thereof.

Representative of the methods is indirect one including modifications thereof, consisting of adding an acetylenic anion to a carbonyl compound followed by rearrangement to desired a,fl-unsaturated aldehyde, for example, as illustrated by the following reaction sequence.

[G. Saucy et al., Helv. Chim. Acta, 42, 1952 (1959)]. However, these methods are disadvantageous in requirement of multi-step reactions or in low yield or in limitation of application.

Alternative most striking methods are so-called aldol-condensation consisting of condensing an active methylene group adjacent to an aldehyde group with another carbonyl group.

In general, the various methods for reacting the compounds involving an active methylene group adjacent to the electron withdrawing group (e.g. nitro group, carbonyl group, sulfonyl group, a carboxylic acid ester,

cyano group etc.) with other carbonyl compounds have been known as well as that of the active methylene group adjacent to aldehyde (aldol-condensation).

However, these reactions are accompanied by sidereactions undesirable for the objective reaction in many cases, such as self-condensation or polymerization, since the reactions are usually carried out in the presence of a basic catalyst. In order to remove these side-reactions, various methods, for example, Mannich reaction, Darzen condensation, Reformatsky reaction, have been reported. However, the satisfactory process for formyl-olefination has been unknown.

On the contrary, the process for preparing olefins consisting .of reacting a carbonyl compound with a phosphonium ylide compound, so-called Wittig reaction, is very useful reaction for introducing the terminal methylene to carbonyl group or further increasing the hydrocarbon chain as well as Grignard reaction. Attempts to apply this reaction to the aldol-condensation type reaction, for example, the reactions by the ylide compounds involving the electron withdrawing group adjacent to the methylene group in the opposite side against the phosphonium group, as indicated by the formulae II V, have been known. However, the nucleophilicity of the reagents to the carbonyl compounds decreases due to the electron-delocalization, for

example, as indicated in the following equation. Accordingly, the reactivity of the reagents is remarkably low in comparison with the Wittig reagents involving no electron withdrawing group in the adjacent position. For example, the above-described compound V reacts with benzaldehyde to yield cinnamic aldehyde, while not react with ketones. Furthermore, the compound V does not react with an aldehyde located at the sterically hindered position (e.g. an aldehyde located at the tertiary position) [Trippett and Walker, J. Chem. Soc., i266 (1961)].

Wadsworth and his co-workers developed the reaction method using phosphonate carbanion as a modification of the Wittig reaction [1. Am. Chem. Soc., 83, i733 (1961)]. This reaction may be characterized by utilizing the phosphonate carbanion more reactive than the Wittig reagent in order to increase the reactivity of the active methylene compounds involving the electron withdrawing group in the adjacent position. For example, the reactivity of the reagents represented by the following formulae Vl IX, involving the electron withdrawing group in the adjacent position, could considerably be increased [Bose and Dahill, Jr., Tetrahedron Letters, 959 (1963); ibid., J. Org. Chem., 30, 505 (1965); Takahashi and Ohta, Bull. Chem. Soc. Japan, 35, 1498 (1962); Normant, Comptes Rendus, 256, i800 (1963)]. However, these compounds, particularly, the compound IX utilizable as a reagent for preparing a,B-unsaturated aldehyde is readily inactivated in the presence of a basic catalyst by the reaction sequence as follows:

Therefore, in spite of these various attempts, the sufficient process for formyl-olefination has not yet been developed.

The present inventors had studied various methods in order to remove these disadvantages and it has been discovered that the enamine-type phosphonate compounds represented by the above-described general formula I have been excellently effective as reactive agents for preparing a,B-unsaturated aldehyde by condensing aldehydes involving the active methylene group at the a-position with other carbonyl compounds. The reactive agents of the present invention may be applied to all sorts of carbonyl compounds ineluding aldehydes and ketones and effectively show remarkable reactivity even to the hindered carbonyl compounds such as aldehydes located at the tertiary position. Furthermore, the method of the present invention is much more effective than the abovementioned other methods in stability of the reagents in reaction medium, in casiness of the reaction procedure, in improvement of the yield or in stereospecificity.

Each substituent of the reagents represented by the above-mentioned general formula I is more precisely indicated as follows: R represents a lower alkyl group such as methyl, ethyl, n-propyl, n-butyl or the like, R has the same meaning as R or is a member selected from the group consisting of a lower alkyl group such as methyl, ethyl, n-propyl, n-butyl or the like, an aralkyl group of seven to eight carbon atoms such as benzyl, phenylethyl, tolubenzyl or the like, and an aryl group of six to seven carbon atoms such as phenyl, tolyl or the like, R is a member selected from the group consisting of an acyclic or cyclic alkyl group of one to six carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t pentyl, n-hexyl, cyclopentyl, cyclohexyl or the like, and an aryl group of six to seven carbon atoms, and R is a member selected from the group consisting of a hydrogen atom, a lower alkyl group such as methyl, ethyl, npropyl, i-propyl, n-butyl, n-pentyl, n-hexyl or the like, an aralky] group of seven to eight carbon atoms such as benzyl, phenylethyl, tolubenzyl or the like, a lower vention are:

Dimethylphosphonoacetaldehyde methylamine enamine,

Dimethylphosphonoacetaldehyde i-propylamine enamine,

Dimethylphosphonoacetaldehyde t-butylamine enamine,

Dimethylphosphonoacetaldehyde cyclohexylamine enamine,

Diethylphosphonoacetaldehyde methylamine en amine,

Diethylphosphonoacetaldehyde i-propylamine enamine,

Diethylphosphonoacetaldehyde t-butylamine enamine,

Diethylphosphonoacetaldehyde cyclohexylamine enamine,

Diethylphosphonoacetaldehyde aniline enamine, Di-n-propylphosphonoacetaldehyde t-butylamine enamine, Di-n-propylphosphonoacetaldehyde amine enamine, 2-Dimethylphosphonopropiona]dehyde t-butylamine enamine, 2-Dimethylphosphonopropionaldehyde cyclohexylamine enamine, 2-Diethylphosphonopropionaldehyde enamine, 2-Diethylphosphonopropionaldehyde amine enamine, 2-Diethylphosphono-n-butyraldehyde enamine, Z-Diethylphosphono-n-butyraldehyde amine enamine, 2-Diethylphosphono-n-valeraldehyde enamine, 2-Diethylphosphono-n-valeraldehyde amine enamine, 2Diethylphosphono-3-phenylpropionaldehyde cyclohexylamine enamine, 2-Diethylphosphono-3-(N-cyclohexyl)aminoacrylic acid ethyl ester, 2-Diethylphosphono-Z-bromoacetaldehyde hexylamine enamine, 2-Diethylphosphono-2-chloroacetaldehyde butylamine enamine, Ethyl-2-cyclohexylaminovinyl phenylphosphinate, Ethyl-l-methyl-2-cyclohexylaminovinyl phenylphoscyclohexylt-butylamine cyclohexylt-butylamine cyclohexylt-butylamine cyclohexylcyclophinate,

Ethyl-l-ethyl-2-cyclohexylaminovinyl phenylphosphinate,

Ethyl-( l-benzyl-2-cyclohexylamino )vinyl phenylphosphinate,

Ethyl-2-t-butylaminovinyl phenylphosphinate, Ethyl-( l-methyl-2-t-butylamino)vinvyl phenylphosphinate, Ethyl-( l-benzyl-2-t-butylamino)vinyl phinate, Ethyl-2-tbutylaminovinyl ethylphosphinate, and Ethyl-Z-cyclohexylamino ethylphosphinate. The reagents (l) of the present invention may be prepared from the compounds of the general formula X as illustrated by the following reaction sequence,

phenylphos- P- =CH-NH-R IP91??? bu .abydwsewwm In I) wherein R, R R and R each has the same meanings as described above.

The compounds (X) in the above-described reaction sequence may be prepared according to the known method as follows:

wherein R and R each has the same meanings as described above, the acetal derivative of a-bromoacetaldehyde of the general formula XII is subjected to reaction with the phosphite derivative of the general formula XI and then the acetal protecting group of the resulting phosphonate or phosphinate derivative (XIII) is removed to the compound (X).

The reagents (Ia: R=H in I) can be prepared by reacting the compounds (X) with the primary amines represented by the general formula R NI-I in a suitable solvent (e.g. methanol, ethanol, n-propanol, tbutanol, benzene, toluene, tetrahydrofuran etc.) or without any solvent at a temperature ranging from C to 120C. The reaction may be carried out according to the process for preparing so-called Schiff-base or the process for enamine formation.

The reagents (Ib: R =R" but a hydrogen atom in I) can be prepared by further reacting the compounds (Ia) with the compounds, capable of releasing the radical R represented by the general formula R X in the presence of a catalyst.

The compounds of the general formula R X are alkyl halogenides consisting of an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, nhexyl or the like and a halogen atom such as chlorine, bromine or iodine atom (e.g. methyl iodide, ethyl bromide, n-butyl iodide, n-hexyl bromide etc. aralkyl halogenides consisting or an aralkyl group such as benzyl, phenylethyl, tolubenzyl or the like and a halogen atom (e.g. benzyl chloride, phenylethyl bromide, tolubenzyl iodide etc.), lower alkoxycarbonyl halides such as methyl chloroformate, ethyl chloroformate or the like, and halogenating agents. The halogenating agents in this process mean the reagents producing the positively charged halogen atom in the reaction medium, for example, chlorine (Cl bromine (Br iodine (I cyanogen bromide, cyanogen iodide, N-bromoacetamide (NBA), N-bromosuccinimide (NBS), N- chlorosuccinimide (NCS), N-chloro-ptoluenesulfonamide (chloramine-T), N-

chlorobenzenesulfonamide (chloramine-B), t-butyl hypochlorite, pyridinium bromide perbromide and the like.

The reaction of the compounds (Ia) with the compounds R X is usually carried out in a suitable inert solvent in the presence of a catalyst under cooling or at room temperature (about 30 40C), is necessary, under heating (such as refluxing temperature). The catalysts used in the reaction are, for example, lithium, sodium, lithium hydride, sodium hydride, sodium amide, potassium amide, Grignard reagents such as ethylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride and the like, and organo metal compounds such as butyl lithium, phenyl lithium and the like. The preferred solvents are ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diglyme and the like, and hydrocarbon solvents such as benzene, toluene, xylene and the like.

The resulting reagents (I) of the present invention may be applied to preparation of a,B-unsaturated aldehydes (XIV) increasing two carbon atoms from carbonyl compounds as illustrated by the following reaction sequence:

RI c=0 r ole-4:110

is usually carried out in an aprotic solvent in the presence of a basic catalyst. The usual reaction procedure may be indicated as follows: the reagent represented by the general formula (I) is dissolved in an aprotic solvent with a basic catalyst to form the anion represented by the following general formula:

wherein R R R and R each has the same meanings as described above, and then the starting carbonyl compound is added to this solution. However, the reaction is not always carried out according to such successive procedure. For example, the reaction may also be carried out by adding the basic catalyst into the previously prepared solution of the starting carbonyl compound and the reagent (l) in an aprotic solvent.

The basic catalysts used are metal alcoholate such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, sodium t-butoxide and the like, sodium amide, potassium amide, lithium diethylamide, sodium hydride, lithium hydride, lithium triphenylmethide, methyl lithium, butyl lithium or Grignard reagents such as methylmagnesium bromide, ethylmagnesium bromide and the like.

Aprotic solvents, i.e. the solvent releasing no proton, are, for example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like, hydrocarbon solvents such as benzene, toluene, xylene and the like, N,N-dimethylformamide and the like.

The reaction temperature may be set according to the reactivity of the carbonyl compounds applied and the reaction may be carried out at room temperature or under cooling or sometimes under heating. Moreover, the reaction is preferably carried out under an inert gas such as nitrogen or argon, because of the reaction in the presence of a strongly basic catalyst. Furthermore, the reaction is preferably carried out under stirring in order to effectively proceed the reaction.

The products obtained in the above-described process are the Schiff-bases involving the partial structure represented by the general formula XV,

wherein R and R each has the same meanings as described above. Accordingly, the products must be hydrolyzed as usual manner with an acid or base to regenerate the aldehyde group. In general, the products without the isolation as the intermediates are preferably subjected to the acid hydrolysis consisting of the two phase system. The preferred acid medium is a diluted solution of oxalic acid or a buffer solution such as acetic acid-sodium acetate-water, tartaric acid-sodium tartarate-water or the like.

Thus resulting a,B-unsaturated aldehydes (XIV) may be isolated and purified according to the usual isolation and purification procedure used in the general synthetic chemistry, for example, extraction, distillation, recrystallization, column chromatography, thin layer chromatography, gas chromatography, or the methods by so-called carbonyl reagents (e.g. Girard reagents, hydrazone, semicarbazone, oxime etc.).

The invention will be better explained by the following examples which are not intended as a limitation thereof.

Example 1 Diethylphosphonoacetaldehyde Enamine To a solution of 30.2 g of diethylphosphonoacetaldehyde in 90 ml of anhydrous methanol, there is added 19.2 ml of purified cyclohexylamine in nitrogen atomosphere under ice-cooling and stirring. The reaction mixture is kept at room temperature for 10 minutes under stirring and then the solvent is distilled off under reduced pressure. The residue is dissolved in 150 ml of anhydrous ether, dried over anhydrous potassium carbonate, and then evaporated under reduced pressure.

Cyclohexylamine The resulting residue is purified by highly vacuum distillation in the presence of 300 mg of potassium carbonate to afford 33.06 g of diethylphosphonoacetaldehyde cyclohexylamine enamine (75.4 percent yield) having bp. 151 l52C/0.04 mmHg. The purity of this substance is confirmed by gas chromatography. UV: k,,,,,,'" 241 mp. (5 16,300). 1R: v fl 3255, 1633 (shoulder), 1620, 1211, 1058, 1035, 955 cm. NMR: 8(CC1.,) 1.25 (triplet), 3.25 (multiplet), 3.85 (multiplet), 6.7 (multiplet) ppm. Anal. Calcd. for C,,H ,,O NP: C, 55.15; H, 9.26; N, 5.36; P, 11.86. Found: C, 54.54; H, 9.55; N, 5.43; P, 12.08.

Example 2 According to the same procedure as Example 1, dimethylphosphonoacetaldehyde t-butylamine enamine, diethylphosphonoacetaldehyde t-butylamine enamine, ethyl-2-cyclohexylaminovinyl phenylphosphinate, and ethyl-2-t-butylaminovinyl ethylphosphinate are prepared, respectively.

Example 3 2-Diethylphosphonopropionaldehyde amine Enamine To a solution of 10.0 g of diethylphosphonoacetaldehyde Cyclohexylamine enamine in 30 ml of anhydrous tetrahydrofuran, there is added dropwise 22.0 ml of ethylmagnesium bromidetetrahydrofuran solution (2.31 mM/ml) within a period of 20 minutes under icecooling and stirring. After stirring for 40 minutes at room temperature, a solution of 8.10 g of methyl iodide in 10 ml of anhydrous tetrahydrofuran is added dropwise and then the reaction mixture is refluxed for 1.5 hours. After cooling, the reaction mixture is poured into ice-water, extracted with dichloromethane-ether (1 3), washed with saturated sodium chloride aqueous solution and then evaporated under reduced pressure to yield 7.09 g of residue, which onlcrystallization from ether-pentane affords 7.00 g of 2-diethylphosphonopropionaldehyde cyclohexylamine enamine (66.6 percent yield) having mp. 61 64C/73C (double melting point). UV: A 246 my. (e 24,200). IR: v a

Cyclohexyl- 3265, 1642, 1221, 1057, 1031, 951 cm. Anal. Calcd. for C H O NP: C, 56.71; H, 9.52; N, 5.09; P, 11.25. Found: C, 56.52; H, 9.59; N, 5.25; P, 11.20.

Example 4 2-Diethylphosphono-3-phenylpropionaldehyde Cyclohexylamine Enamine To a solution of 2.85 g of diethylphosphonoacetaldehyde cyclohexylamine enamine in 10.0 ml of anhydrous tetrahydrofuran, there is added dropwise 6.86 ml of 2.39N ethylmagnesium bromide-tetrahydrofuran solution within a period of 10 minutes under ice-cooling and stirring. After stirring for 1 hour under ice-cooling, a solution of 1.38 g of benzyl chloride in 4.0 ml of anhydrous tetrahydrofuran is added dropwise within a period of 5 minutes and then the reaction mixture is refluxed for 22 hours. After cooling, the reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 3.09 g of residue, which on crystallization from ether-pentane affords 2.72 g of 2-diethylphosphono-3- phenylpropionaldehyde cyclohexylamine enamine (71.2 percent yield) having mp. 79 82C. UV: A 246.5 mp. (e 15,960). 1R: v 'a 3406, 1636, 1603, 1235, 1057, 1031, 950 cm. Anal. Calcd. for c,,i-i,,,o,NP; C, 64.93; H, 8.61; N, 3.99; P, 8.82. Found: C, 65.35; H, 8.92; N, 4.04; P, 9.16.

Example According to the same procedure as Examples 3 and 4, 2-diethylphosphonopropionaldehyde t-butylamine enamine, ethyl-l-methyl-2-cyclohexylaminovinyl phenylphosphinate, and ethyl(1-benzyl-2- cyclohexylamino)vinyl phenylphosphinate are prepared, respectively.

Example 6 2-Diethylphosphono-3-(N-cyclohexyl)aminoacrylic Acid Ethyl Ester To a solution of 4.00 g of diethylphosphonacetaldehyde cyclohexylamine enamine in 12.0 ml of anhydrous tetrahydrofuran, there is added dropwise 9.6 ml of 2.39N ethylmagnesium bromide-tetrahydrofuran solution within a period of minutes under icecooling and stirring. After stirring for 1 hour at room temperature, a solution of 1.65 g of ethyl chlorofor mate in 10 ml of anhydrous tetrahydrofuran is added dropwise within a period of 5 minutes under icecooling and then the reaction mixture is stirred for additional 3 hours at the same temperature. The reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 4.37 g of residue, which on purification by highly vacuum distillation affords 4.12 g of 2-diethylphosphono-3-(N- cyclohexyl)aminoacrylic acid ethyl ester (80.4 percent yield) having bp. 110 147C/0.002 0.003 mmHg. UV: k f 240, 274 mp. (e 12,500, 9,130). 1R: v 3431, 3271, 1725, 1686, 1661, 1616 cm. Anal. Calcd. for c,,H,,o,NP: C, 54.04; H, 8.47; N, 4.20; P, 9.29. Found: C, 54.04; H, 8.63; N, 4.02; P, 9.64.

Example 7 2-Diethylphosphono-Z-bromoacetaldehyde hexylamine Enamine To a solution of 5.00 g of diethylphosphonoacetaldehyde cyclohexylamine enamine in 15.0 ml. of anhydrous tetrahydrofuran, there is added dropwise 1 1.3-ml of 2.39N ethylmagnesium bromide-tetrahydrofuran solution within a period of 10 minutes under ice-cooling and stirring. After stirring for 30 minutes at room temperature, a solution of 2.02 g of cyanogen bromide in 100ml of anhydrous tetrahydrofuran is added dropwise within a period of 5 minutes under ice-cooling and then the reaction mixture is stirred for 2.5 hours at room temperature. The reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 5.96 g of crude crystals, which on recrystallization from ether-pentane afford 4.94 g of 2-diethylphosphono-2-bromoacetaldehyde cyclohexylamine enamine (75.8 percent yield) having mp. 79 80C. UV; k,,,,,, 245 my. (6 16,700). 1R: v,,,,,,' 3371, 1635, 1242,1056, 1031, 962 cm". Anal. Calcd. for C H O NPBrz C, 42.36; H, 6.81; N, 4.12; P, 9.11; Br, 23.49. Found: C, 42.26; H, 2.06; N, 4.24; P, 9.84; Br, 23.62.

Example 8 5B -Formylethy1ene-6B-vinyl-B-nor-androstan-3a-ol To a mixture of 386 mg of 52.9 percent sodium hydride and 1.5 ml of tetrahydrofuran, there is added a solution of 2.221 g of diethylphosphonoacetaldehyde cyclohexylamine enamine in 14.5 ml of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for minutes. A solution of 1.19 g of 5fi-formyl-6B-vinyl-B-nor-androstan-3a-ol benzo- Cycloate in 7.0 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 3.5 hours under stirring. Further, 300 mg of paraformaldehyde is added under ice-cooling and the reaction mixture is stirred for 30 minutes, then poured into ice-water, and extracted with etherdichloromethane (4 l). The extract is washed with saturated sodium chloride aqueous solution and the solvent is evaporated to dryness to yield 2.686 g of residue. To a solution of this residue in 25 ml of benzene, there is added 1.7 g of oxalic acid and ml of water. After the solution is kept overnight at room temperature under stirring, the benzene layer is separated and the aqueous layer is extracted with etherdichloromethane (6 l). The extract combined with the benzene layer is washed with saturated sodium chloride aqueous solution and then the solvent is evaporated to dryness to yield 1.658 of residue. The residue is dissolved in 130 ml. of methanol and heated with 40 ml of 2N-p0tassium carbonate solution for 20 minutes under refluxing. The reaction mixture is concentrated under reduced pressure, poured into ice-water and then extracted with ether-dichloromethane (4 1). The extract is evaporated under reduced pressure to yield 1.339 of residue, which is passed through a column of 30 g of silica gel (containing 3 percent of water). Eluate with benzene-chloroform (1:1) is recrystallized from ether-pentane to afford 840 mg of 5B- formylethylene-6B-vinyl-B-nor-androstan-3a-ol (87 percent yield) having mp. 62 65C.

Example 9 3-Formylmethylene-5 a-androstan- 1 76-01 Benzoate To a mixture of 73 mg of 52.9 percent sodium hydride and 1.0 ml of tetrahydrofuran, there is added a solution of 398 mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.0 ml of anhydrous tetrahydrofuran under ice-cooling and'stirring, and then the stirring is continued for 15 minutes. A solution of 500 mg of 17B-benzoyloxy-5a-androstan-3-one in 4.0 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 3.5 hours under stirring. The reaction mixture is poured into ice-water and the product is extracted with ether, washed with water and evaporated to dryness to yield 782 mg of residue. To a solution of this residue in 30 ml of benzene, there is added 800 mg of oxalic acid and 90 ml of water. After the solution is kept at room temperature for 17 hours under stirring, the benzene layer is separated and the aqueous layer is extracted with ether. The extract combined with the benzene layer is washed with water and evaporated to dryness to yield 551 mg of crystalline residue, which on recrystalli zation from ether affords 426 mg of 3-formylmethylene- 5a-androstan-l7B-ol benzoate percent yield) having mp. 157 158C. UV: k 236 mp. (e 21,700). 1R: u '4 2783, 1683, 1632 cm. NMR: 8 (CDCI 5.82 (doublet), 10.30 (doublet) ppm. Anal. Calcd. for c u o z C, 79.96; H, 8.63. Found: C, 79.49; H, 8.68.

Example 10 3 fl-Hydroxy- 1 7(20 )-5 a-pregnen-Z 1 -al To a mixture of 59.7 mg of 52.9 percent sodium hydride and 1.0 ml of tetrahydrofuran, there is added a solution of 342 mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.0 ml of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. A solution of 164 mg of 3B-tetrahydropyranyloxy-Sa-androstan-l7-one in 1.5 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for hours under stirring. The reaction mixture is poured into ice-water and the product is extracted with ether, washed with water and evaporated to dryness to yield 343 mg of residue. To a solution of this residue in I). ml of benzene, there is added 445 mg of oxalic acid and 36 ml of water. After the solution is kept at room temperature for 22 hours under stirring, the benzene layer is separated and the aqueous layer is extracted with ether. The extract combined with the benzene layer is washed with 2N hydrochloric acid and then with water and evaporated to dryness to yield 208 mg of residue. The residue is dissolved in 20 ml of 70 percent acetic acid and heated at 60 70C for 30 minutes. The reaction mixture is evaporated under reduced pressure, poured into ice-cooled saturated potassium carbonate aqueous solution and then extracted with ether. The extract is washed with water and evaporated to dryness to yield 132 mg of crude crystals, which on recrystallization from dichloromethane-ether afford 99 mg of 3B-hydroxy-17(20)-5a-pregnen-21-al (71.2 percent yield) having mp. 176 180C. UV: k,,,,,,,"" 245 my. (a 14,500. IR: v a 2758, 1669, 1640, 1610 cm. NMR: 8 (CDCI 5.69 (multiplet), 9.78 (doublet) ppm. Anal. Calcd. for C H O z C, 79.70; H, 10.19. Found: C, 79.07; H, 10.12.

Example 1 1 Sa-Formylethylenepregnane-3,20-dione To a mixture of 105 mg 52.9 percent sodium hydride and 0.5 ml of tetrahydrofuran, there is added a solution of 605 mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 1.0 ml of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for minutes. Then a solution of 100 mg of 3,3:20,20-bisethylenedioxy-Sa-formylpregnane in 2.0 ml of anhydrous tetrahydrofuran is added and the resulting solution is refluxed for 9 hours. Thereafter, according to the same procedure as Example 3, the reaction product is treated with 840 mg of oxalic acid and 30 ml of water and then with 30 ml of 70 percent acetic acid. Thus resulting product is crystallized from ether to afford 71 mg of 5a-formylethylenepregnane-3,20- dione (82.7 percent yield) having mp. 140 144C. UV: k 220.5 my. (6 13,850). IR: v fl 2736, 1695, 1623 cm". NMR: 8 (CDC1 6.13 (quartet, J =16 cps), 7.27 (doublet, J =16 cps), 9.52 (doublet) ppm. Anal. Calcd. for C H O C, 77.80; H, 9.25. Found: C, 77,80; H, 9.25.

Example 12 17(20)-5a-Pregnen-21-al To a mixture of 99 mg of 52.9 percent sodium hydride and 1.4 m1 of tetrahydrofuran, there is added a solution of 568 mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.2 ml of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. Then, a solution of 200 mg of 5a-androstan-l7-one in 1.4 ml of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 10 hours. The reaction mixture is treated as usual manner, and the product is dissolved in 35 m1 of benzene. The solution, to which is added 1.05 g of oxalic acid and 105 ml of water, is kept at room temperature for 13 hours under stirring. Thereafter, the product worked up as usual manner is crystallized from ether to afford 162 mg of 17(20)-5apregnen-21-al (74.0 percent yield) having mp. 150 152C. UV: k 245 mp. e 16,500). 1R: v,,,,, 2758, 1 670, 16 40 1610 cm. NMR: 8 (CDCl l 5.73 (multiplet), 9.87 (doublet) ppm. Anal. Calcd. for C ,H O: C, 83.94; H, 10.73. Found: C, 83,60; H,

Example 13 Cinnamic Aldehyde To a mixture of 653 mg of 52.9 percent sodium hy dride and 6.5 ml of tetrahydrofuran, there is added a solution of 3.76 g of diethylphosphonoacetaldehyde cyclohexylamine enamine in 20 ml of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. Then, a solution of 1.27 g of benzaldehyde in 13 ml of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 2 hours under stirring. Thereafter, the product worked up as usual manner is purified by vacuum distillation to afford 1.22 g of cinnamic aldehyde (77.2 percent yield) having bp. 78C/1.0 mmHg. UV: A 287 mp. (1 22,400). 1R: v j 1692. lo ers Semicarbazone: mp 206 209C. UV: A 312 mu 34,900). Anal. Calcd. for C H ON C, 63.47; H, 5.86; N, 22.21. Found: C, 63.42; H, 5.85; N, 22.44.

Example 14 3,3-Ethylenedioxy-l lB-hydroxy-5,17(20)- pregnadien-Zl-al To a mixture of 39 mg of 52.9 percent sodium hydride and 0.5 m1 of tetrahydrofuran, there is added a solution of 226 mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 1.5 ml of anhydrous tetrahydrofuran under ice-cooling and stirring. and then stirring is continued for 15 minutes. Then, a solution of mg of 3,3-ethylenedioxy-l IB-hydroxy-S- androsten-17-one in 1.0 ml of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 19 hours under stirring. The reaction mixture is poured into ice-water, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 234 mg of residue. The residue is dissolved in a mixture of dichloromethane and tetrahydrofuran (5 1) and treated with a buffer solution (pH 4.1 prepared from 10 ml of 0.385M tartaric acid and 10 ml of 0.385M sodium hydroxide, at room temperature for 38 hours under stirring. The reaction mixture is poured into water, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 149 mg of residue, which is passed through a column of 3 g of alumina. Eluate with benzene or benzene-dichloromethane (l 1) is recrystallized from dichloromethane-ether to afford 69 mg of 3,3-ethylenedioxy-l 1B-hydroxy-5,17(20)-pregnadien- 21-a1 having mp. 224 226C. Anal. Calcd. for C H 0 C, 74.16; H, 8.66. Found: C, 73,94; H, 8.63.

Example 15 Cyclohexylidene Acetaldehyde According to the same procedure as the above examples, cyclohexanone is subjected to reaction with diethylphosphonoacetaldehyde cyclohexylamine enamine to yield cyclohexylidene acetaldehyde having bp. 88 89C/16 mmHg. UV: k f 240 my. (6 15,200). 1R: v h 1682 cm. NMR: 6 (CDC1 6.86, 9.93 ppm. From the signals of IR and NMR spectra, the contamination of a small quantity of deconjugated aldehyde, i.e. cyclohexenyl acetaldehyde, is recognized.

Thus resulting oily cyclohexylidene acetaldehyde is then subjected to reaction with sodium acetate and semicarbazidehydrochloride in ethanol to yield the semicarbazone (86.4 percent yield from cyclohexanone) having mp. 212 213C. UV: k f' 273.5 my. (6 34,000).

Example 16 2-Cyclohexylidenepropionaldehyde To a mixture of 82 mg of 52.9 percent sodium hydride and 0.5 ml of tetrahydrofuran, there is added a solution of 497 mg of 2-diethylphosphonopropionaldehyde cyclohexylamine enamine in 1.0 ml of anhydrous tetrahydrofuran under ice-cooling. and stirring. The

stirring is continued for minutes and a solution of 147 mg of cyclohexanone in 1.0 ml of anhydrous tetrahydrofuran is then added. The reaction mixture is kept at room temperature for 5.5 hours under stirring and then poured into ice-water. The product is extracted with ether washed with saturated sodium chloride aqueous solution, then the basic portion extracted with 20 percent tartaric acid. To the tartaric acid layer is added potassium carbonate under ice-cooling to be slightly basic. The precipitated product is extracted with ether, washed with saturated sodium chloride aqueous solution and evaporated to dryness to yield crude crystals, which on recrystallization from etherpentane afford the intermediary Schiff-base having mp. 77 78C. UV: A 246.5 mp. (e 24,200). 1R: v fl 2664, 1632, 1614 cm. Anal. Calcd. for C, H N: C, 82.13; H, 11.49; N, 6.38. Found: C, 82.00; H, 11.69; N, 6.15.

To a solution of this intermediary Schiff-base in 23 ml of benzene, there is added 718 mg of oxalic acid and 70 ml of water and the solution is then refluxed for 1 hour under nitrogen atmosphere. After cooling, the benzene layer is separated and the aqueous layer is extracted with ether. The extract combined with the benzene layer is washed with 2N sodium carbonate and saturated sodium chloride aqueous solution and evaporated to dryness to yield 152 mg of residue. The residue is purified by vacuum distillation to afford 129 mg of 2-cyclohexylidenepropionaldehyde (62.6 percent yield from cyclohexanone) having bp. 60C/0.10 0.15 mmHg (bath temperature). On the other hand, the residue obtained by the reaction with oxalic acid, without distilling, may be immediately converted to the 2,4-dinitrophenylhydrazone as crystals having mp. 187 190C in 66.2 percent yield from cyclohexanone. 2,4-Dinitrophenylhydrazone: recrystallized from dichloromethane-ethanol. UV: k f' 'i 223 my. (6 13,400), 259 (14,750), 295(8,900), 389 (25,600). IR: v 3292, 1619,1596, 1334, 1137, 834 cm. Anal. Calcd. for C, H, O N C, 56.59; H, 5.70; N, 17.60. Found: C, 56.50; H, 5.70; N, 17.40.

Example 17 2-Cyclohexylidene-3-phenylpropionaldehyde To a mixture of 187 mg of 52.9 percent sodium hydride and 1.5 ml of tetrahydrofuran, there is added a solution of 2.905 g of 3-phenyl-2-diethylphosphonopropionaldehyde cyclohexylamine enamine in 4.0 ml of anhydrous tetrahydrofuran under ice-cooling and stirring. The stirring is continued for 15 minutes and a solution of 405 mg of cyclohexanone in 4.0 ml of anhydrous tetrahydrofuran is then added. The reaction mixture is refluxed for 3 hours. After cooling, the reaction mixture is poured into ice-water, extracted with ether, washed with saturated sodium chloride aqueous solution and evaporated to dryness to yield 2.496 g of resi' due. A portion (1.704 g) of this residue is dissolved in 50 ml of benzene and treated, according to the same procedure as Example 9, with 3.63 g of oxalic acid and 146 ml of water to yield 1.271 g of residue. The residue is passed through a column of silica gel (Woelm; containing 10 percent of water) and eluted with benzene or benzene-dichloromethane (1 1) to afford 408 mg of cyclohexylidene-3-phenylpropionaldehyde (67.3 percent yield), which is identified as 2,4-dinitrophenylhydrazone having mp. 162 174C (recrystallized from dichloromethane-ethanol). IR: A,,,,,,-"' 3294, 1613. 1594,1515,1326,1134, 835 cm". Anal. Calcd. for C H O N C, 63.94; H, 5.62; N, 14.21. Found: C, 63.64; H, 5.66; N, 14.50.

Example 18 3,3-Ethylenedioxy-1 l-oxo-5,17(20)-pregnadien- To a mixture of 26.9 mg of 52.9 percent sodium hydride and 0.4 m1 of anhydrous tetrahydrofuran, there is added a solution of mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 1.0 ml of anhydrous tetrahydrofuran under ice-cooling and stirring. The stirring is continued for 15 minutes and a solution of 68 mg of 3,3-ethylenedioxy-5-androstene- 11,17-dione in 0.7 m1 of anhydrous tetrahydrofuran is then added. The reaction mixture is kept at room temperature for 21 hours under stirring and then poured into ice-water. The product is extracted with ether, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 171 mg of residue. The residue is dissolved in 3.0 ml of benzene and then 1.088 g of sodium acetate, 480 mg of acetic acid and 3.0 ml of water are added. The resulting mixture is kept at room temperature for 21 hours under stirring and the product is extracted with ether, washed with water and evaporated to dryness to yield 126 mg of residue, which is passed through a column of4 g of alumina. Eluate with benzene or benzene-dichloromethane is recrystallized from dichloromethane-ether to afford 53.2 mg of 3,3-ethylenedioxy-1 1-oxo-5,17(20)-pregnadien- 21-al (72.8 percent yield) having mp. 208 212C. [01],, 47.6 :t 2.2 (c 0.397: chloroform). Anal. Calcd. for C I-1 0 C, 74.56; H, 8.16. Found: C, 74,29; H, 8.14.

Example 19 1-Formy]methylene-6-methoxytetraline To a mixture of 155 mg of 52.9 percent sodium hydride and 1.0 ml of tetrahydrofuran, there is added a solution of 892 mg of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.0 m1 of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. A solution of 200 mg of 6-methoxy-a-tetralone in 2.0 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 6.5 hours under stirring. The reaction mixture is then poured into icewater, extracted with ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 790 mg of syrupy residue. The residue is dissolved in 29 ml of benzene and then 868 mg of oxalic acid and 86 ml of water are added. The mixture is kept at room temperature for 13 hours under stirring and then extracted with ether. Ether extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 114 mg of crystalline residue, which on recrystallization from dichloromethane-ether affords 34 mg of 1'formylmethylene-6- methoxy-tetraline (31 percent yield) having mp. 89 90C. IR: )t 2774, 1656, i 1610, 1591, 1151 cm. Anal. Calcd. for C H O C, 77.20; H, 6.98. Found: C, 76.85; H, 7.01.

Example According to the similar procedure as described above, a-(2,6,6-trimethyl-l-cylohexenyl)- acetaldehyde is converted to a-(2,6,6-trimethyl-lcyclohexenyl)-a-methylcrotonic aldehyde (bp. 99 103C/0.5 mml-lg; identified as Semicarbazone: mp. 155 157C), cinnamalacetaldehyde to 7-phenylheptatrienal (mp. 114 116C), and 2,7-dimethylocta-2,6- dien-4-yne-1,8-dial to 4,9-dimethyldodeca-2,4,8,10- tetraen-6-yne-1,l2-dial (mp. 162 163C), respectively.

Example 21 Cinnamic Aldehyde To a mixture of 590 mg of 52.9 percent sodium hydride and 6.0 ml of tetrahydrofuran, there is added a solution of 3.80 g of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 20 ml of anhydrous tetrahydrofuran and then the mixture is stirred for 20 minutes. A solution of 1.06 g of benzaldehyde in 11 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 4 hours under stirring. The reaction mixture is then added into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and evaporated to yield 3.16 g of residue. To a solution of this residue in 100 ml of benzene, there is added 1.0 g of oxalic acid and 300 ml of water and the solution is then stirred for 14 hours at room temperature. Benzene layer is separated and the aqueous layer extracted with ether. The extract combined with the benzene layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 1.37 g of residue, which on purification by vacuum distillation affords 0.96 of cinnamic aldehyde (72.5 percent yield) having bp. 78C/l.0 M mmHg.

Example 22 a-Methylcinnamic Aldehyde To a mixture of 318 mg of 52.9 percent sodium hydride and 3.0 ml of tetrahydrofuran, there is added a solution of 2.15 g of ethyl-(2-cyclohexylamino-lmethyl)vinyl phenylphosphinate in 12 ml of anhydrous tetrahydrofuran, and then the mixture is stirred for 20 minutes. A solution of 530 mg of benzaldehyde in 5.0 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 20 hours under stirring. According to the same procedure as Example 21, the reaction mixture is treated and then hydrolyzed with oxalic acid. The resulting product is purifed by vacuum distillation to afford 469 mg of a-methylcinnamic aldehyde (64.3 percent yield) having bp. 131 l32C/l.6 mml-lg, identified as semicarbazone: mp. 206 208C. Anal. Calcd. for C H ON C, 65.00; H, 6.45; N, 20.68. Found: C, 65.13; H, 6.29; N, 20.51.

Example 23 ,G-Phenylcynnamic Aldehyde To a mixture of 318 mg of 52.9 percent sodium hydride and 3.0 ml of tetrahydrofuran, there is added a solution of 2.05 g of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 1 1 ml of anhydrous tetrahydrofuran,

and then the mixture is stirred for 20 minutes. A solution of 91 1 mg of benzophenone in 9.0 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 8 hours under stirring. According to the same procedure as Example 21, the reaction mixture is treated and then hydrolyzed with oxalic acid. The resulting product is recrystallized from petroleum ether to afford 655 mg of B-phenylcynnamic aldehyde (63.0 percent yield) as yellowish crystals having mp. 44.0 45.5C. IR. u 2750, 1655, 1600,1580,1235,1155,1135, 870 cm. Anal. Calcd. for C, H, O: C, 86.51; H, 5.81. Found: C, 86.66; H, 5.90. Semicarbazone: mp. 214 215C.

Example 24 2-Cyclohexylidenepropionaldehyde To a mixture of 218 mg of 52.9 percent sodium hydride and 2.0 ml of tetrahydrofuran, there is added a solution of 1.23 g of ethyl-(2-cyclohexylamino-1- methyl)vinyl phenylphosphinate in 5 ml of anhydrous tetrahydrofuran, and the mixture is stirred for 20 minutes. A solution of 294 mg of cyclohexanone in 3.0 ml of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 7 hours under stirring. The reaction mixture is poured into icewater, extracted with ether, washed with saturated sodium chloride aqueous solution and further extracted with 20 percent tartaric acid solution to remove the basic portion. The tartaric acid layer is treated with potassium carbonate under ice-cooling to make slightly basic. The product is then extracted with ether, washed with saturated sodium chloride aqueous solution and evaporated to dryness to yield crude crystals, which on recrystallization from ether-pentane afford the Schiffbase intermediate, having mp. 77 78C, which is identical with an authentic specimen prepared in Example 16.

According to the same procedure as Example 16, this intermediate is hyrolyzed with oxalic acid in benzene and the product is purifed by vacuum distillation to afford 324 mg of 2-cyclohexylidenepropionaldehyde (58.8 percent yield) which is identified as 2,4-dinitrophenylhydrazone (mp. 187 190C).

Example 25 3-Formylmethylene-Sa-androstan-l7B-ol Benzoate To a mixture of 59 mg of 52.9 percent sodium hydride and 1 ml of tetrahydrofuran, there is added a solution of 380 mg of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 2.0 ml of anhydrous tetrahydrofuran, and the mixture is then stirred for 20 minutes. A solution of 395 mg of 17,6-benzoyloxy-5a-androstan-3-one in 3.0 ml of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 6.5 hours under stirring. According to the same procedure as Example 21, the reaction mixture is treated and then hydrolyzed with oxalic acid. The resulting product is recrystalized from ether to afford 298 mg of 3- formylmethylene-Soz-androstan-17B-ol benzoate (71.0 percent yield), having mp. 157 158C, which is identical with an authentic specimen prepared in Example 9.

Example 26 17(20 )-5 a-Pregnen-Z 1 a1 Reaction of 5a-androstan-l7-one with ethyl-2- cyclohexylaminovinyl phenylphosphinate, according to the same procedure as Example 25, affords 17(20)-5apregnen-21-al' (recrystallized from ether) having mp. 150 152C in about percent yield, which is identical with an authentic specimen prepared in Example 12.

Example 27 Sa-Formylethylenepregnane-3,20-dione According to the same procedure as Example 25, 3,- 3:20,20-bisethylenedioxy-Sa-formylpregnane is subjected to reaction with ethyl-2-cyclohexylaminovinyl phenylphosphinate. Hydrolysis with oxalic acid and subsequent deketallization with 70 percent acetic acid at 60 70C afford a-formylethylenepregnane-3,20- dione having mp. 140 144C in about 75 percent yield, which is identical with an authentic specimen prepared in Example 11.

Example 28 2-Cyclohexylidene-3-phenylpropionaldehyde To a mixture of 364 mg of 52.9 percent sodium hydride and 3.5 ml of tetrahydrofuran, there is added a solution of 3 .07 g of ethyl-(1-benzyl-2- cyclohexylamino)vinyl phenylphosphinate in 4.0 ml of anhydrous tetrahydrofuran under ice-cooling and stirring, and the mixture is then stirred for minutes. A solution of 393 mg of cyclohexanone in 4.0 ml of anhydrous tetrahydrofuran is added and the resulting solution is refluxed for 4 hours. After cooling, the reaction mixture is poured into ice-water, extracted with ether, then treated in the same manner as Example 21, and then further hydrolyzed with oxalic acid. The product is purified by passing through a column of silica gel to afford 41 1 mg of 2-cyclohexylidene-3- phenylpropionaldehyde (48.1 percent yield), which is converted to 2,4-dinitrophenylhydrazone identical with an authentic specimen prepared in Example 17.

Example 29 3,3-Ethylenedioxy-1 l-oxo-5,l7(2l )-pregnadien- To a mixture of 136 mg of 52.9 percent sodium hydride and 1.0 ml of tetrahydrofuran, there is added a solution of 880 mg of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 7 ml of anhydrous tetrahydrofuran, and the mixture is then stirred for 20 minutes under ice-cooling. A solution of 340 mg of 3,3- ethylenedioxy-S-androstene-l 1,17-dione in 3 ml of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 24 hours under stirring. The reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over an hydrous sodium sulfate and evaporated to dryness to yield 930 mg of residue. To a solution of this residue in 16 ml of benzene, there is added 5.3 g of sodium acetate, 2.31 g of acetic acid and 16 ml of water, and the resulting mixture is kept at room temperature for 21 hours under stirring. The product is extracted with ether, washed with water and evaporated to dryness to yield a residue, which on crystallization, from dichloromethane-ether affords 263 mg of 3,3- ethylenedioxy-l 1-oxo-5,17(20)-pregnadien-2l-al (71.0 percent yield) having mp. 208 212C, which is identical with an authentic specimen prepared in Example 18.

We claim: 1. A compound of the formula:

wherein R is a lower alkyl group, R is a member selected from the group consisting of R'O, a lower alkyl group, an aralkyl group of seven to eight carbon atoms and an aryl group of six to seven carbon atoms, R is a member selected from the group consisting of an acyclic or cyclic alkyl group of one to six carbon atoms and an aryl group of six to seven carbon atoms, and R is a lower alkoxycarbonyl group.

2. A compound according to claim 1, namely 2- diethylphosphono-3-(N-cyclohexyl)aminoacrylic acid ethyl ester. 

2. A compound according to claim 1, namely 2-diethylphosphono-3-(N-cyclohexyl)aminoacrylic acid ethyl ester. 